From the Green lab, Clinical Research Division

Jan. 15, 2018

- AS Kuhlmann

In pre-targeted radioimmunotherapy, the antibody is administered first, followed by administration of a clearing agent to remove any unbound antibody and finally injection of the radiolabeled isotope, in this case yttrium-90-DOTA. This strategy considerably reduces toxicities. The newly engineered bispecific antibody binds both to the CD38 protein (blue) whose expression is commonly increased on multiple myeloma cells, and to the radiolabeled element (black).

Figure provided by Dr. Damian Green.

Pretargeted radioimmunotherapy (PRIT) combines antibody-mediated immunotherapy with targeted delivery of radioisotopes. It is a multi-step process, first the administration of a monoclonal antibody, followed by a clearing agent to remove any unbound antibody. Then, a radiolabeled element is injected for antibody binding and specific elimination of the targeted cancer cells. Radioimmunotherapy has the potential to improve cancer treatment by increasing specific tumor cell eradication and reducing toxicity. Radioimmunotherapy has already been successful for leukemia and lymphoma treatments but evaluation in the context of multiple myeloma (MM) has been very limited.

In a recent study published in the journal Blood, the groups of Drs. Damian Green and Oliver Press assessed radioimmunotherapy applied to MM by targeting CD38, a protein whose expression is increased, stable and uniform in MM cells. CD38 has already successfully been targeted with monoclonal antibody imediated immunotherapy. However, relapses remain inevitable with the current approaches.

In the study, a newly designed bispecific antibody binding both to the CD38 antigen on one extremity and to a radiolabeled isotope on the other extremity was characterized. Two versions of the bispecific antibody were evaluated side by side. The first version, previously developed by Dr. Green’s lab contained a streptavidin to bind to the exogenously administered radiolabeled biotin conjugate. However, the competition between endogenous and exogenous biotin was considered a potential limitation to the therapeutic efficiency of the antibody. To eliminate this competition the authors, in collaboration with partners at the Massachusetts Institute of Technology, designed the bispecific construct, which replaced streptavidin by a region binding to yttrium-DOTA (yttrium-90 being the radioactive substance and DOTA the chelating agent). Dr. Green explained, “We have previously demonstrated the efficacy of pretargeted radioimmunotherapy (PRIT) using a streptavidin-biotin system, however the current anti-CD38 bispecific pretargeting construct obviates theoretical concerns regarding endogenous biotin blocking and greatly reduces concerns about immunogenicity”.

After being validated in vitro for expression, radioisotope and antigen binding the new CD38 PRIT bispecific antibody was further evaluated in vivo using immunodeficient mice xenografted (graft of tumor cells from a different species) with MM tumor cell lines and compared with the biotin binding antibody. Mice were injected with the antibody first, followed by the clearing agent at 23 hours and radiolabeled element injection one hour later. The radiolabeled anti-CD38 PRIT antibody was specifically retained in tumor tissues relative to healthy tissues. Tested with different doses of radionuclide (600, 1000 or 1200 µCi), animals receiving CD38 bispecific antibodies demonstrated 100% complete remissions within 12 days. Ultimately more than 75% of the tumor-bearing mice were cured and survived more than 150 days, while the untreated or control treated mice died within 30 days. Additionally, when used with lower doses of the radionuclide the new CD38 bispecific antibody performed better than the streptavidin-biotin antibody. Sixty-one percent of the mice treated with the new antibody survived at 600 µCi relative to 22% of the mice treated with the streptavidin-biotin antibody. Similarly, at 1000 µCi, 78% of the mice treated with the new antibody survived relative to 47% of the mice treated with the streptavidin-biotin antibody. Dr. Green added, “the head-to-head studies described in our Blood paper demonstrate efficacy that is equivalent or superior to the excellent results we have demonstrated with streptavidin-biotin PRIT. We believe that innovations that improve targeting and diminish toxicity, while emphasizing the unique favorable attributes associated with RIT, will help to encourage adoption of the approach”.

Indeed, this study further demonstrates the potential of pretargeted radioimmunotherapy to improve MM treatment. This method could also be applied to many other cancer types as evidenced by the fact that in the current paper, the authors also demonstrate the efficacy of targeting CD38 with their bispecific approach in a non-Hodgkin lymphoma model. Dr. Green added, “We have recently shown that parallel bispecific antibodies targeting CD20 in B cell lymphoma can eliminate disease in preclinical models (Green DJ. et al. Cancer Research. 76(22):6669-6679, 2016) and Johnnie Orozco MD, PhD (Assistant Member) is preparing a manuscript describing a bispecific approach to target AML. Our future studies will investigate potential synergy of PRIT with small molecule inhibitors, radiosensitizing agents and a role for bispecific PRIT in stem cell transplantation. Ultimately, well-designed clinical trials recapitulating the responses seen in our preclinical models would provide the most compelling argument for the adoption of bispecific PRIT”, before concluding, “We are very excited to move forward with our bispecific construct in clinical trials for patients with multiple myeloma and B cell lymphomas. We are working to secure funding from donors, grantors and industry to support these efforts”.

This study was funded by the National Institutes of Health, National Cancer Institute, by Multiple Myeloma Opportunities for Research and Education (MMORE), the Brotherton Family Fund, the Seattle Translational Tumor Registry (STTR) and the David and Patricia Giuliani Family Foundation.

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